Phthalic anhydride (PA): a valuable substrate in organic transformations

This review has been centralized on applications of phthalic anhydride (PA) as a valuable and significant heterocyclic substrate in two- and multicomponent organic reactions. The article has been subdivided into the following parts: (i) PA introduction by focusing on its characterization, synthesizing procedure, and multiple-aspect applications. In addition, the previous review articles based on PA have also been indicated; (ii) the applications of PA as a substrate have been subdivided into parts with a glance on the reaction components numbers; (iii) the applications of PA in esterification reactions; and (iv) some examples of PA in multistep synthesis. The review covers the corresponding literature up to the end of 2022. According to the abovementioned classifications, PA is a potent substrate to design a wide range of heterocyclic compounds that possess various kinds of properties and applications in chemistry, industry, and pharmaceuticals.


Introduction
2-Benzofuran-1,3-dione (isobenzofuran-1,3-dione, 1,3-isobenzofuranidone, 1,3-dioxophthalan, phthalandione, 1,3phthalandione, 1,2-benzenedicarboxylic acid anhydride, phthalic acid anhydride, 1,2-benzenedicarboxylic anhydride, 1,3-dihydro-1,3-dioxoisobenzofuran) with the common/popular name of phthalic anhydride (PA) is a versatile organic compound with the formula C 6 H 4 (CO) 2 O. It is a white (or somehow colorless) powder (or akes and sometimes needles) with a melting point of 131°C, molar mass of 148.1 g mol −1 , and some acidic odor. Actually, this fused bicycle with the LD 50 = 1.530 mg kg −1 (oral rat) is the anhydride form of phthalic acid. It is soluble in ethanol, acetone, water, and benzene but sparingly in ether and chloroform. 1 Contact with skin and eye may cause an allergic skin reaction and serious eye damage. Basketter and Kimber published a review article in 2016, in which the absence of both skin-and respiratory-sensitizing capacity of PA was conrmed based on interpreting predictive toxicology tests for skin sensitization. 2 This white solid was rst synthesized by Auguste Laurent in 1836. The rst procedure involved liquid-phase mercurycatalyzed oxidation of naphthalene. 3 In the modern process, vanadium pentoxide was used as the catalyst in a gas-phase reaction with naphthalene using molecular oxygen. 4 Rindone group in 2010 prepared PA via the ozonation of naphthalene. 5 An alternative synthetic procedure is also based on the oxidation of o-xylene by vanadium-based catalysts such as V 2 O 5 / TiO 2 and anatase-supported vanadium oxide. [6][7][8] In 2018, Co-Mn/H 3 PW 12 O 40 @TiO 2 was also utilized as the catalyst for the selective vapor-phase oxidation of o-xylene to PA in the presence of green oxidant. 9 Boger and Menegola also used extruded monoliths with high thermal conductivity as improved operated and economic catalysts to prepare PA from the oxidation of oxylene. 10 This technology was also studied in detail by Tronconi group in 2012. 11 The air oxidation of o-xylene over mesoporous V-Mo-MCM-41 molecular sieves was also applied for PA synthesis by Selvaraj and Lee in 2005. 12 PA can be also produced from phthalic acid. 13 Nikolov's research group published a review article on the synthesis of PA from o-xylene in detail. 14 Dias and Portela in 1997 issued a review article that discussed about various catalysts to gain PA from two main routes for its synthesis, which concerns the oxidation of o-xylene and naphthalene. 15 Recently some green and novel protocols have been presented to obtain PA such as renewable production from biomass-derived furan and maleic anhydride. 16 Deng group in 2021 also reported green production of PA from biobased furan and maleic anhydride by an acid resin catalyst. 17 PA obtained renewably form 5-hydroxymethfurfural (HMF) using MoO 3 / Cu(NO 3 ) 2 as a catalyst. 18 Sha group in 2016 designed a conceptual process to prepare PA from corn stover, an agricultural residue. Their techno-economic assessment contends energy integration alternatives as well as water consumption and life cycle greenhouse emissions. 19 Ierapetritou and coworkers in 2015 accounted a novel route for PA production from hemicellulose solutions, in which they focused on synthetic process, technoeconomic analysis, and life cycle assessment (LCA) of the protocol. 20 Kinney and Pincus in 1951 reported PA production from catalytic air oxidation of some substrates such as certain higher aromatics and coal tar fractions. 21 The PA synthesis by the oxidation of tar oils was also represented by Shelmerdine's group in 1953. 22 Prichard in 1956 obtained PA from the reaction of bromobenzene and carbon monoxide in the presence of sodium carbonate and nickel carbonyl. 23 Zazhigalov and Kiziun in 2017 reported PA production by Diels-Alder reaction during n-pentane oxidation on vanadium phosphorus oxide (VPO) catalyst. 24 Kim and Yang in 2000 studied the synthesis of maleic and phthalic anhydrides from the mixture of cyclopentene and 1-pentene via their selective oxidations under different reaction parameters. 25 In 1919, Gibbs published the title "phthalic anhydride. Iintroduction", which discussed the different synthetic procedures of PA. 26 Gibbs in 1920 also interpreted the title "history of the preparation and properties of pure phthalic anhydride". 27 The chemical engineering design of the PA preparation reactor is considered based on the computer model that simulates the operation of the reactor over a range of conditions that lead to both satisfactory mass transfer and heat transfer requirements. 28 Wainwright and Foster in 1979, reviewed the "catalysts, kinetics, and reactor design in phthalic anhydride synthesis". 29 PA has been utilized in different elds of science and technology. In polymerization technologies, some examples such as preparation of ternary polymeric system including polysulde (PS), diglycidylether of bisphenol A resin, and PA have been reported. PA plays a role in the curing reaction of this ternary polymer. 30 The copolymerization of PA with epoxides catalyzed by amine-bis(phenolate)chromium(III) complexes also performed in 2021. 31 Amin's group in 2011 prepared two hyperbranched polyesteramides (HB1 and HB2) by the bulk reaction between PA and diisopropanolamine (DiPA) or diethanolamine (DEA), respectively. The effects of various solutions of HB1 and HB2 on the properties (such as measurements of water of consistency, setting times, bulk density, apparent porosity, and compressive strength for the cement pastes) of ordinary Portland cement (OPC) and Portland limestone cement (PLC) were studied. 32 Duchateau's group constructed a partially renewable polyester via the catalytic ring-opening copolymerization of limonene oxide and PA. 33 Pooley and coworkers in 2005 copolymerized PA as an electrophilic monomer with aziridine or 2-methylaziridine as nucleophilic monomers in the absence of initiator under various experimental conditions. 34 PA was utilized as a bridge for the graing of chitosan biopolymer onto wool fabric to prepare antibacterial agents. 35 It also played a role in the chemical modication of chitosan to obtain bacteria inhibitors. 36 In 2020, a novel biodegradable diblock/triblock poly(ester-bicarbonate)s was prepared from cyclohexene oxide (CHO), propylene oxide (PO), PA, and CO 2 in a one-pot/one-step protocol. 37 The surface modication of silk ber using PA to gra the polysaccharide chitosan has been reported in 2009, which lead to the dyeing ability of the graed silk. The graed samples possess antibacterial potential. 38 PA is also a critical substrate to prepare a series of new optically active and thermally stable polyamides (PAs). 39 It plays the role of a chain end group in the uorescent PMMAs polymers. These polymers can detect the intermacromolecular reaction in reactive polymer blends at a low concentration using uorescence-gel permeation chromatography. 40 It has also utilized as a key substrate for the multistep preparation of novel optically active polyamides derived from 5-(3-methyl-2-phthalimidylpentanoylamino)isophthalic acid. 41 PA was also utilized for the preparation of chiral polyesters through enantioselective terpolymerization with racemic and mesoepoxides and also sequence-controlled block copolymers. 42 PA was also applied as a modier in poly(butylene succinateco-butylene adipate) (PBSA)/cellulose nanocrystal (CNC) composites. The modied PBSA/CNC composites demonstrated elevated mechanical properties, fast crystallization, and improved hydrophobicity. 43 PA has been added in the preparation procedure of poly(butylenes succinate)/cellulose nanocrystals (PBS/CNC) composite via melt blending, which yielded higher crystallinity and smaller crystals. 44 To obtain phthalylated cellulosic compounds with higher DS (degree of substitution), the chemical modication of sugarcane bagasse cellulose has been reported with PA in the 1-butyl-3-methyl imidazolium chloride solvent and 4-dimethylaminopyridine (DAMP) catalyst. 45 PA is also signicant in different elds of biological and pharmaceutical applications. It is a key substrate in the synthesis of symmetrical novel organoselenocyanates and diselenides dye stuffs, which was evaluated for the antitumor properties. 46 In 2012, N-benzoyl 3-nitro-phthalimide, which possesses anxiolytic activity in mice model, was prepared from PA as the substrate. 47 Bis[aqua-1,8-(1,2-dicarboxamido benzene)3,6-diazaoctane copper(II)/nickel(II)] tetrachloride, as two binuclear complex, was synthesized by a two-component one-pot metal template condensation between PA and 1,8-diamino-3,6-diazaoctane. The complexes are able to bind to calf thymus (CT)-DNA under physiological pH. 48 Lepoittevin et al. in 2021 investigated the reactivity of PA as a chemical respiratory sensitizer toward reconstructed human epidermis (RHE). 49 Spanedd and Bourel-Bonnet published a review article about the potential of cyclic anhydrides such as PA in bioconjugation to functionalize the biomolecules and carriers. The pHdependent stability and reactivity, as well as the physical properties, can be tuned by the structure of the cyclic anhydride used. Thus, their application in smart delivery systems has become very important. 50 Alheety in 2021 prepared new complexes of PA (as ligand) with some cations (such as Co(II), Ni(II), Cu(II), Mn(II), and Zn(II)) in 1 : 1 molar ratio. The microbicide activity studies of the synthesized complexes against four types of bacteria (E. coli, S. epidermidis, K. pneumoniae, and S. aureus) was also reported. The complexes also demonstrated stability on laser beams for 10-30 s. 51 Marzouk's group in 2016 designed and manufactured some new phthalazinones containing benzyl moiety via a multistep reaction started from PA. Some of the heterocycles demonstrated antitumor activity. 52 Yamaguchi and coworkers in 1998 constructed some 2-[2-(L-imidazolyl)alkyl]-1(2H)-phthalazinones as novel antiasthmatic agents with dual activities of thromboxane A2 synthetase inhibition and bronchodilation. 53 Costa Silva group in 2021 modied Chicha gum with PA to obtain a new biologically active material that demonstrated excellent inhibitory effect against P. aeruginosa and K. pneumoniae species (rating 100% inhibition) and could also inhibit Escherichia coli growth. 54 Bold et al. in 2000 synthesized new anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. The key substrate for the preparation procedure starts from PA. 55 PA also has a special role in sensors. In 2016, phthaloylchitosan (PHCS) was synthesized simply and cost-effectively using chitosan and PA by microwave irradiation, which was applied to determine tyrosine with high sensitivity and good selectivity through carbon nanotube lm-coated glassy carbon electrode. 56 Zhang et al. in 2022 reported a novel phthalic anhydride-based room-temperature phosphorescence (RTP) emitter with the lifetime longer than one second. 57 A novel uorescent probe IMPD, based on imidazo[1,2-a] pyridine that contained PA moiety in its structure, was designed and synthesized by Huang's research group in 2021. The probe could detect hydrazine via its maleimide as the recognition group. In addition, the probe IMPD could dye the HepG2 cell with blue color in the presence of hydrazine. 58 Another notable application of PA is in the dye industry. It utilized to prepare the nanosized copper phthalocyanin blue (CuPc) pigments. 59 The phenol precipitation and dye bleaching capabilities of phthalic anhydride-modied horseradish peroxidase C (PA-HRP) were also investigated in 2000. 60 Polymeric surfactants have been synthesized by the reaction of maleic anhydride (MA), polyethylene glycol (PEG), and PA, which exhibit excellent surface-active properties (including surface tension, low-foaming, solubilization, and dispersant properties) in disperse dye systems. 61 PA also plays a role in separation and waste removal. In 2016, the Gurgel group prepared chemically-modied sugarcane bagasse, named as carboxylate-functionalized sugarcane bagasse (SPA), via the reaction of PA with sugarcane bagasse. The SPA adsorbent was used to remove Co 2+ , Cu 2+ , and Ni 2+ from aqueous solution in mono-and multicomponent systems in the batch mode. 62 Another aspect of the PA usage is in the eld of catalyst and protecting group. It was utilized as a part of the co-catalytic system (in combination with Zn(OTf) 2 ) to promote Beckmann rearrangement. 63 The efficient and clean oxidation of suldes to sulfones (not the probable sulfoxide) with urea-hydrogen peroxide in the presence of PA in ethyl acetate was also performed in 2018. 64 PA also worked as a remarkable protective group in the synthesis of a dipeptide (b-alanine-L-histidine) via two procedures, which are solution phase peptide synthesis (SPS) and solid phase peptide synthesis (SPPS). 65 Liu et al. in 2017 utilized PA as a low-temperature activator in the H 2 O 2 bleaching system for cotton fabric. The performance of the H 2 O 2 /PA bleaching system was investigated by measuring the CIE whiteness index (WI) of the bleached cotton fabric, H 2 O 2 decomposition rate, and bursting strength, respectively. 66 Maldas and Kokta in 1990 considered the performance of PA as a coupling agent in wood ber-lled polystyrene composites. Its presence evaluated the mechanical properties of the composite materials. 67 Duan in 2019 interpreted PA-promoted ring-opening cationic polymerization of cyclohexene oxide catalyzed by dinuclear chromium complex supported by piperazine-bridged [ONSO] ligand to obtain atactic poly(cyclohexeneoxide) polymer. The formation of carbocation species by interaction between PA and bimetallic chromium complexes is the real initiator center. 68 The hydrogenation of PA is another important reaction that has been evaluated extensively. Liquid phase selective hydrogenation of PA to phthalide (an important industrial intermediate for pharmaceuticals, ne chemicals, and organic synthesis) was reported in 2015 in the presence of Au/FeO x -TiO 2 catalyst. 69,70 Liquid phase hydrogenation of PA to phthalide over Au/TiO 2 catalysts (with different gold loadings) was reported in 2009. 71 Different catalytic systems were reported for PA hydrogenation to phthalide, such as acid-tolerant intermetallic cobalt-nickel silicides as noble metal like catalysts, 72 CoSi x / CNTs, 73 hydrophobic activated carbon supported Ni-based acidresistant catalyst, 74 and Al 2 O 3 -supported NiCu alloy. 75 PA is applicable in some other elds as well. Al-Sawaad and Alwaaly research group in 2021 reported bisthioureaphthalatonickel(II) complex (PTUNi) via the reaction of NiCl 2 -$6H 2 O with thiourea (2 mol) and PA (1 mol). The complex was evaluated as a corrosion inhibitor for carbon steel alloy (C1010) against a corrosive medium of 0.1 M hydrochloric acid at 298 K. 76 Fouda group in 2013 also reported anhydride derivatives (such as PA) as corrosion inhibitors for carbon steel in hydrochloric acid solutions. 77 In 2022, glycerol/PA novel nanocomposite was introduced for microwave absorbing applications. 78 Velayutham and coworkers in 2009 demonstrated the synthesis and characterization of polyurethane (PUR) coatings derived from polyols synthesized with glycerol, PA, and oleic acid. The utilized polyols were designated as Alk28, Alk40, and Alk65, in which 28%, 40%, and 65% of oleic acid was present, respectively. The coatings obtained from polyol Alk28, with the lowest percentage of oleic acid content, exhibited the best overall physicochemical properties, followed by Alk40. PUR from polyol with the highest percentage of oleic acid content, Pualk65 coatings, were soer and their anticorrosive properties were less satisfactory. 79 Son in 1975 studied the role of PA in cure retardation of rubbers. 80 Based on the importance of PA in diverse elds of science and technology, many review articles have been written. Dubey and coworkers in 1996 published a review article about the importance of phthalic anhydride as a petrochemical agent. 81 In 2002, a review article entitled "Some new applications of phthalic anhydride in organic synthesis" was published by the Iordache research group. 82 In 2021, Elgharbawy reported a miniarticle entitled "A review on phthalic anhydride industry and uses". 83 In 2016, Basketter and Kimber discussed about PA as a chemical allergen in detail. They claimed that it displays a differentiated behavior, whereas most respiratory sensitizers are known also to give rise to delayed skin reactions; evidence for PA suggests that it only causes immediate type allergy. 84 Siddiqui and Javed research group study the computational, spectroscopic, Hirshfeld surface, electronic state, and molecular docking properties (with 21 different protein receptors) of PA. 85 Hong et al. in 2017 investigated the antiinammatory effect of titrated extract of Centella asiatica in PA. 86 In 1977, a patient with occupational asthma caused by PA was reported. 87 Yanagimoto in 1956 discussed about the reaction between urea and PA under pressure. 88 The Martin group in 2015 published a book-chapter entitled "Anhydride-based multicomponent reactions", which contains some reactions of PA. 89 2. Applications of PA in twocomponent reactions Katritzky and Yates in 1976 prepared 6H-benzimidazo[1,2-b] [2,4]benzodiazepine-7,12-dione (3) via the catalyst-free reaction of PA (1) and 2-aminobenzimidazole (2) (Scheme 1). 90 Gitis group in 2000 reported the reaction of PA with 2methylimidazole that formed amide. 91 The authors also examined the reaction of maleic anhydride that leads to the formation of molecular complexes.
Hajipour et al. in 2000 interpreted the phthloyation microwave-assisted reaction of PA (1) with amino acids (4) under solvent-free conditions to obtain phthalimide derivatives without racemization (5) (Scheme 2). 92 The substrates were mixed with silica gel and irradiated with microwave (900 W) for an appropriate time.
Billman and Harting in 1948 obtained the phthalyl derivatives of different kinds of amino acids (5) via the reaction of PA (1) with (4) at 180-185°C within 15 min with 30-92% yield. 93 Zeng research group in 2004 also reported the N-phthaloylation of amino acids (Gly, Ala, Phe, Val, 10 mmol) with PA or phthalic acid (11 mmol) with amino acids at 130-135°C under pressure (about 40 mmHg) for 15-30 min with 79.4-90.5% yield. 94 Kidd and King in 1948 also reported the preparation of phthalyl-Lglutamic acid. 95 Leite et al. in 2014 demonstrated the microwave-assisted synthesis of some phthaloyl amino acids from the reaction of PA (1) and amino acids (4, Gly, Ala, Val, Glu, Phe, Ile, and Trp) in a 1 : 1 molar ratio in TEA or 4-DMAP (0.5 mL) and DMF (three drops) within 2 min by 31.9-96%. The products presented antioral inammatory activity comparable to thalidomide. Most of the compounds effectively suppressed nitric oxide production in murine cells stimulated with lipopolysaccharide. 96Ö kten and coworkers in 2022 reported the facile, expeditious, and cost-effective preparation of N-phthaloyl (S)-amino acids and evaluated their in silico activities against Staphylococcus aureus. 97 In 1958, the reaction of PA with different amino acids by reuxing in nonpolar solvents (such as benzene and toluene) in the presence of triethylamine was performed. By separating the water formed in the reaction, the phthalimide derivatives were prepared in good yields and without racemization. Phthaloylation without racemization may also be carried out in N,Ndimethylformamide medium. 98 Homsi and Kasideh in 2015 obtained N-phthalimide amino acids from PA and amino acids (Gly, Ala, Phe, Val, Leu, and Asp) in reuxing glacial AcOH for 2 h with 66.8-95.8% yield. The synthesized compounds, which were puried through recrystallization from ethanol, were screened for their antimicrobial activity against four microorganisms, namely, Streptococcus epidermidis, Escherichia coli, Mycobacterium tuberculosis, and Candida albicans. 99 Safari et al. in 2009 achieved quinophthalone pigments (7) through the reaction of PA (1) and 2-methylquinolines (6) in the presence of BF 3 /Et 2 O as the catalyst under solvent-free and reux conditions (Scheme 3). 100 Loghmani-Khouzani in 2004 also gained some quinophthalones (7) via the microwave-assisted (700 W) reaction of PA (1) and 2-methylquinolines (6) in a 1 : 1 molar ratio in the presence of silica gel (silica gel 60, 230-240 mesh Merck, 300 mg) within 2 min by 85-97%. 101 Phillips and Goss in 1926 obtained methyl-isopropylquinoline yellow (11) through the reaction of PA with methylisopropyl-quinaldine (10). The product (10) was also achieved from 2-amino-p-cymene (8) and paraldehyde (9) (Scheme 4). 102 Safari et al. in 2012 performed simple regioselective onepot solvent-free reaction of 2-methylpyridines (12) and PA (1) in the presence of BF 3 $nano SiO 2 (as a solid supported catalyst) at conventional heating and also under microwave irradiation to prepare the corresponding pyrophthalones (13) (Scheme 5). 103 in 1 mmol amount, similar to the other two substrates, but according to the proposed mechanism (Scheme 8) and also the products structure, its role is just that of a promoting agent. According to the mechanism, the rst step is the formation of 1,3-dipolar intermediate (A), which attacked PA (1) to obtain zwitterionic intermediate (B), which cyclized to the spiro intermediate (D). Water attack to the positively charged phosphorus ion of (D) formed (F), followed by a proton transfer and loss of Ph 3 PO, which led to product (18). In pathway A, intermediate (D) was attacked by the alkoxy anion, and the subsequent loss of Ph 3 P gave compound (19).
Aliabadi's group in 2014 obtained a series of phthalimides (23) through the reaction of PA (1) and anilines (21) in toluene solvent (reux, 24 h) in the presence of Et 3 N with 21-80% yield. The antiepileptic activity of the products was investigated using two experimental models, namely, maximal electroshock (MES) and pentylenetetrazole (PTZ), and the obtained results were compared with diazepam as the reference drug. The neurotoxicity of the compounds was also evaluated using the rotarod model. The presence of para-methoxy substituent in the product showed anticonvulsant activity in the MES (maximal electroshock) model. None of the tested compounds demonstrated acceptable protection in subcutaneous PTZ (pentylenetetrazole) model. 110 Patel's group in 2022 achieved some new classes of isoindoline-1,3-diones (23) via the reaction of PA (1) and the primary amino-containing compounds (21) in reuxing glacial acetic acid as the solvent-catalyst within 3 h with 62-78% yield. The quantum chemistry-based investigations of the products as antimycobacterial agents (toward the H37Rv strain by a dual read-out assay method) was also performed. Computational studies such as density functional theory (DFT) study, molecular docking, and dynamic simulation studies illustrated the reactivity and stability of the synthesized compounds as InhA inhibitors. 111 Hamdi et al. investigated some phthalimides via the reaction of PA (1) and amines (21) (aromatic, aliphatic, and benzylic) in 1 : 1.1 molar ratio in the presence of p-TSA (50 mg) in reuxing toluene within 3 h with 29-88% yield. The synthesized compounds were screened for their antimicrobial activities against Gram-positive bacterial strains (Micrococcus luteus, Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus), a Gram-negative bacterial strain (Salmonella typhimurium), and a fungus (Candida albicans). The cytotoxicity studies of the phthalimides were conducted in two human cancer cell lines, namely, MDA-MB-231 and MCF-7. 112 Al-Mousawi in 2010 achieved 2-phenylisoindole-1,3-dione (23) via the reaction of PA (1) and aniline (21) under solventfree conditions for 30 min in a focused microwave oven at 160°C with 96% yield. 113 Singh Bisht and Rajat Bisht in 2021 reported the reaction of PA with some amines (such as urea, glycine, aniline, and sulphanilic acid) to yield various phthalimide derivatives (23) using domestic microwave with 70.7-80.21% yield. All synthesized derivatives were subjected to DDPH scavenging activity, which showed good to high antioxidant potential (69.56%) in the presence of ascorbic acid as the standard. 114 Hassanzadeh's group in 2017 supplied cyclic imides. In the rst step, PA (1) reacted with glycinamide (26) in freshly distilled and dried pyridine under reux conditions to yield the corresponding amic acid (27) within 5 h. The amic acid underwent ring closure with acetic anhydride and anhydrous sodium acetate to form imides (28,29), which were isolated via column chromatography (Scheme 13). 116 In another procedure, the reaction of PA and 2-aminobenzylamine (30) in pyridine within 5 h under reux conditions gave the corresponding cyclic imide (31) (Scheme 14). 116 The imides were screened for their antimicrobial activities against three types of bacteria and one type of fungi.
Nie and Liu research group in 2022 provided 2-ethylanthraquinone (2-EAQ) (94) using PA (1) and ethylbenzene (93) as a feedstock by the combination of acylation and dehydration over a Sc-modied Hb catalyst. Sc modication was used to create new strong Lewis acid and increased acid amount of Hb. 141 The catalytic performance of amide-AlCl 3 (DMA-2AlCl 3 ) ionic liquid analogs in synthesizing o-benzoylbenzoic acid (BBA) (96) from PA and benzene (95) was demonstrated. The catalyst was obtained by mixing AlCl 3 and DMA in 2 : 1 molar ratio at 100°C for 3 h. Then, PA and benzene, in a 1 : 10 molar ratio were mixed at 40°C within 5 h to obtain the product by 98.2% (Scheme 36). 142 The authors proposed that Al 2 Cl 7 − , gained from DMA-2AlCl 3 , attacks the anhydride and formed (96) via an electrophilic substitution reaction.
Naphto[1,2-b]thiophene (97) reacted with PA (1) to prepare ketocarboxilic acid (98). Naphto[2,1-b]thiophene (99) also reacted with PA to obtain 2-naphto[2,1-b]thienyl o-carboxyphenyl ketone (100) with 70% yield. The Friedel-Cras reaction between PA and thiophene (101) yielded ketoacid (102) (Scheme 37). 143 Naeimi and Namdari in 2009 described the direct preparation of anthraquinones (94) via the reaction of PA (1) and various benzene derivatives (93) in the presence of anhydrous AlCl 3 (0.11 mmol)/methanesulfonic acid (0.01 mmol) (LAMA) at 95-100°C within 15-65 min with 6-93% yield. Benzenes that contain electron withdrawing substituents (such as nitrobenzene and 1,3-dichlorobenzene) had the lowest reactivity in this reaction (8% and 6% yields, respectively). The compound 1,3dinitrobenzene did not get the corresponding product even performing the reaction overnight. 144 Shaq group in 2021 reported newly synthesized anthraquinone-based pyrimidine derivatives. In the rst step, the authors prepared the anthraquinone derivatives (94) via the modied procedure of Madje et al. 145 in which the PA and benzene derivatives in a 1 : 1.1 molar ratio were mixed in aqueous media at room temperature in the presence of alum (KAl(SO 4 ) 2 $12H 2 O), which was followed by the addition of concentrated HCl, washing with EtOAc, drying, and recrystallization from methanol. In the next step, the pyrimidine derivatives (105) (obtained by a procedure of Shaq et al. 146 ) were obtained via the three-component reaction of benzaldehydes (19), urea (103), and ethyl acetoacetate (104). In the third step, different derivatives of the precursors (94) and (105) were mixed in the presence of catalytic amount of copper chloride and cupric oxide in methanol for 20-30 minutes at ambient temperature to obtain the anthraquinone-based pyrimidines adducts (106-109) (Scheme 38). 147 The antioxidant, antidiabetic, molecular docking, and QSAR studies of the products were also examined.
In addition, McMullen in 1922 studied the Friedel-Cras reaction of PA with benzene in the presence of AlCl 3 in detail. 171 Rahman and Nahar in 1992 studied the reaction of arylcoppermagnesium reagents (prepared from ArMgX and CuI) with one equivalent of PA. The phenylcoppermagnesium reagent (Ar = C 6 H 5 ) gave 2-benzoylbenzoic acid (96) and 3,3-diphenylphthalide (149) in 40% and 42% yield, respectively. The yield of 2benzoylbenzoic acid (96) increased to 93% in the presence of dimethyl sulphide. Under these conditions, no phthalide was formed. On the other hand, lithium diphenylcuprate reacted with PA in ether-hexane to give 2-benzoylbenzoic acid (96) and 3,3-diphenylphthalide (149) in 92% and 7% yields, respectively. The reaction of phenylcopper reagent (prepared from PhMgBr and CuI) and PA under similar conditions proceed slowly to get 2-benzoylbenzoic acid (96) in 15% yield. The reaction of phenylmagnesium bromide in the presence or absence of catalytic amounts of copper(I) iodide led to unsatisfactory results. The use of two equivalents of phenyllithium with one equivalent of PA, on the other hand, afforded 3,3-diphenylphthalide (149) in 77% yield. The authors believed that the species (A) is formed as the rst step. If it is stable, it would be present in the system long enough to undergo an intramolecular ring opening (pathway A) to form 2-aroylbenzoate (C), which hydrolyzed to generate 2aroylbenzoic acid (96). On the other hand, if (A) is very unstable, it may decompose intramolecularly by the transfer of an organic group and concomitant ring opening (pathway B) to produce (B), which converted into the lactone form, which is 3,3-diphenylphthalide (149) either during hydrolysis or by the elimination of metal oxide prior to hydrolysis. Compared with diethyl ether, THF and dimethyl sulphide are expected to have greater stabilizing effects on species (A), presumably by forming more stable complexes; thus, in their presence, the reaction of (A) directed to pathway A. Since dimethyl sulphide is the most efficient of the ligands examined, it is not surprising that the yields of 2-benzoylbenzoic acid are the highest in its presence (Scheme 58). 172 Wang in 2004 accounted an efficient method for the conversion of aldoximes (161) to nitriles (162) via the reaction of PA and aldoximes, in 1.01 : 1 molar ratio, which gained phthalic acid (163) as byproduct (Scheme 59). 173 According to the proposed mechanism, using PA (1)  of the cycloaddition was also achieved using chiral phosphine ligands to provide d-lactones enantioselectively (Scheme 64). 176 Lácová in 1986 considered the reaction of 2-benzothiazolylthioethanoic acid (170)  Meyer and Ryan group in 2015 reported that PA (1 eq) underwent a 1,3-dipolar cycloaddition reaction with N-benzylazomethine ylide (that formed in situ from N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (176) (1.1 eq.) and a catalytic amount of triuoroacetic acid) to produce unstable spiro(isobenzofuran-1,5 ′ -oxazolidin)-3-ones (177), which was reduced with sodium borohydride to afford 1(3H)-isobenzofuranones (178) (Scheme 66). 178 Renfrew and Bostock in 1977 performed the Knoevenagel condensation of PA (1) with ethyl cyanoacetate (112) in the presence of sodium as the catalyst in benzene for 4 h to furnish ethyl cyano(phthalidy1idene)acetate (179) in 95% yield. Utilizing triethylamine as a base in toluene at 90°C for 24 h, a yellow color was produced immediately, and upon reuxing, an intense orange color developed. On cooling, an orange oil separated, which on acidication gave a white solid in 64% yield, identied as (2)-ethyl 2-carbamoyl-8-cyano-3hydroxybenzofulvene-8-carboxylate (180) (Scheme 67). 179 The Ramirez group in 1961 found that triethyl phosphite (181) effected the conversion of PA (1) in a 2 : 1 molar ratio into biphthalyl (182) in satisfactory yield (70%). The reaction was carried out in an excess of the phosphite as the solvent and the biphthalyl separated from the solution in nearly pure state. It was observed that most of the excess triethyl phosphite was isomerized to diethyl ethylphosphonate (183) during the reaction (Scheme 68).   182 Maccioni's group in 2003 also gained the commands (186) via the catalytic role of acetic acid in reuxing isopropyl alcohol media within 1 h with 61-75% yield. 183 The antimicrobial properties of the products was also examined by the authors that was not satisfactory.
Jafarpour and coworkers in 2013 developed a new method for the decarboxylative and decarbonylative addition of cyclic anhydrides to alkynes. They performed the palladium-catalytic benzannulation of PA (1) with alkynes (187) in a 1 : 3 and 1 : 2 molar ratio to obtain the corresponding polyfunctionalized sterically condensed naphthalenes (188) and phenanthrenes (189), respectively. The sequential liberation of CO 2 and CO occurred via the oxidative decomposition of anhydride (Scheme 71). 184 Fardpour et al. in 2019 constructed substituted vinylated phthalides (191) through a ruthenium-catalyzed crossdehydrogenative coupling reaction of PA (1) with acrylates (190) in 1 : 2 molar ratio in the presence of Cu(OAc) 2 $H 2 O as the oxidant in N-methyl-2-pyrrolidone (NMP) solvent (Scheme 72). 185 The reaction proceeded via C-H bond activation through a successive double vinylation accompanied by decarboxylation and annulation reaction.
Silva's research group in 2020 described the solvent-free synthesis of rhodamine dyes (193) via the reaction of PA and m-aminophenols (192) using Nb 2 O 5 as the catalyst. The solvatochromic study of rhodamines was also performed (Scheme 73). 186 Rhodamine dyes possessed various applications due to their properties, such as high molar absorptivity, high uorescence quantum yield, photostability, and absorption and emission wavelengths in the visible region, which make them good candidates in electronic devices (such as lasers and OLEDs).
A novel catalyst obtained via the stabilization of methylene dipyridine nanoparticles on Fe 3 O 4 (Fe 3 O 4 /SiO 2 / propyltriethoxysilane/methylene dipyridine nanoparticles) was prepared by Sadeghzadeh and Nasseri in 2013, which was utilized to prepare pyrazolophthalazinyl spirooxindoles (269) via a four-component solvent-free reaction at room temperature (Scheme 100). 232 Maleki C and ultrasound irradiation at room temperature. 236 The protocol was successful for different classes of aldehydes such as aromatic, cyclic/linear aliphatic, heteroaromatics, and sterically-hindered candidates. An example of their procedure has been demonstrated in Scheme 104 (entry 1). In addition, the catalyst could be successfully recycled and reused at least for six runs without a signicant loss in activity.  (272) using nano g-Al 2 O 3 /BF n /Fe 3 O 4 (8 mg) via the one-step reaction of equimolar of four substrates under solventfree conditions, which yielded the corresponding adducts with 90-97% yield in 10-17 min (Scheme 104, entry 14). 250 The catalyst was recycled by washing with CH 2 Cl 2 , drying at 50°C under vacuum for 1 h, and reused within 5 runs successfully. (O) Liu and Li et al. in 2020 prepared a novel modied core-shell magnetic nanocomposite by anchoring Ag NPs on magnetite core that was coated with chitosan-alginate dual biopolysaccharide (Fe 3 O 4 /CS-Alg/Ag NPs). The novel nanocatalyst was utilized for the synthesis of (272) via one-step and one-pot reaction of the corresponding substrates at 80°C within 0.2-1.5 h with 50-95% yield. The catalyst demonstrated human lung protective effects against a-Guttiferin. These events revealed that the catalyst suppressed Guttiferin-induced cell death in a dose-dependent manner in lung MRC-5, CCD-19Lu, WI-38, and BEAS-2B cell lines. The catalyst was recovered easily using an external magnet and recycled for 10 successive times with minimal reduction in activity (Scheme 104, entry 15). 251 (P) In 2022, Naeimi and Zahedifar reported an immobilized copper(II) complex on microcellulose (cell-DABCO-Cu) as a novel catalyst to promote the preparation of (272) at 80°C under solvent-free conditions in a one-step and one-pot manner (Scheme 104, entry 16). 252  35 min with 89-95% yield (Scheme 104, entry 17). 253 The authors examined the efficacy of the protocol through utilizing succinic anhydride instead of PA. They also prepared phthalazine-diones (271) by the reaction of PA (1), aromatic aldehydes (19), hydrazine hydrate (56), and alkyl cyanoacetates (112) (methyl and ethyl) successfully in the same reaction conditions within 22-37 min with 80-95%. (R) Tigote's group in 2017 used ZnFe 2 O 4 nanoparticles (1.5 mol%) as a catalyst for this transformation via the one-pot and two-step reaction of aromatic aldehyde (19) and the dimedone (261), which was added into the mixture of PA (1) and hydrazine hydrate (56) in a 1 : 1 : 1 : 1.2 molar ratio at room temperature within 30-90 min with 76-89% yield. 254 (S) Mahmoodi's group in 2020 used tetrabutyl phosphonium sulfate ([TBP] 2 SO 4 , 5 mol%) as a novel room-temperature ionic liquid (RTIL) to prepare (272) via the domino reaction of the mentioned four substrates at room temperature within 10-20 min with 89-92% yield. The authors examined the scope of the protocol utilizing succinic anhydride instead of PA. They also achieved phthalazine-diones through the reaction of phthalazine-diones (271) and the reaction of PA (1), aromatic aldehydes (19), hydrazine hydrate (56), and alkyl cyanoacetates (112) (methyl and ethyl) successfully in the same reaction conditions within 15-45 min with 65-92% yield. 255 Some research groups utilized 1,3-cyclohexanedione (273) (in addition with dimedone) to prepare (272) and 3,4-dihydro-1H-indazolo[1,2-b]phthalazine-6,11(2H,13H)-diones (274), which consist of (A). Sadek et al. in 2019 developed a highly efficient, catalyst-free, one-pot, multicomponent synthesis of various indazolophthalazines (272,274) in glycerol as a cheap, biodegradable, and commercially available promoting solvent and catalyst under controlled microwave heating (Scheme 105). 256 The reaction mixture in glycerol was heated under reux in a Milestone microwave lab station at 60°C. They also synthesized (277)  The magnetic catalyst could be separated easily by an external magnet and reused in ve more consecutive runs without much decrease in the catalytic activities. The authors also examined the efficacy of the catalyst in the synthesis of two kinds of phthalazine-diones (271) via the reaction of PA (1), aldehydes (19) (which are 4-chloro-3nitrobenzaldehyde and pentanal), aminonitriles/ethyl cyanoacetate (112), and hydrazine hydrate (56) in a 1 : 1 : 1 : 1.2 molar ratio in the same reaction conditions within 20-25 min with 92-97%. 257 Zaheer et al. in 2016 exploited Pr x CoFe 2−x O 4 (x = 0.1) nanoparticles to catalyze the efficient one-pot four-component reaction of PA (1), hydrazine hydrate (56), dimedone (261), and various quinoline aldehydes (278,279) to achieve phthalazine quinoline derivatives (280, 281) (Scheme 106). 258 The synthesized adducts were evaluated for antibiolm activity against P. aeruginosa and C. albicans.

Applications of PA in esterification
Ahmad et al. in 2010 reported immobilized Candida Antarctica lipase, Novozym 435, as a biocatalyst to catalyze the esterication reaction of PA (1) and betulinic acid (292) to obtain 3-Ophthalyl betulinic acid (293) in n-hexane/chloroform. The effect of different parameters in the reaction process was predicted by the "response surface methodology" (RSM) technique. The comparison of the results of this model and experimental values revealed a good correspondence. The effect of enzyme amount was found to be less, while the reaction temperature, reaction time, and molar ratio strongly affected the ester yield. According to the "central composite rotatable design" (CCRD) optimization, in the presence of a betulinic acid to phthalic anhydride in a 1 : 1.11 molar ratio, the maximal yield of the ester (64.7%) was obtained using 145.6 mg enzyme at 53.9°C in 20.3 h. This predicted that the optimum conditions are in close correlation with the experimental results (Scheme 112). 264 Ahmad's research group in 2010 also considered the reaction parameters of lipase-catalyzed esterication of betulinic acid (292) using PA (1) in organic solvent media. 265 The lipase from Candida antarctica immobilized on an acrylic resin (Novozym 435) was employed for esterication. The inuence of different reaction parameters, such as effect of single and mixed solvents, substrate molar ratio, reaction time, temperature, amount of enzyme, effect of inorganic bases, and effect of substrate support were investigated and optimized. The optimum conditions to obtain 3-O-phthalyl-betulinic acid (293) (61.8%) are: substrate molar ratio (betulinic acid : phthalic anhydride, 1 : 1), within 24 h at 55°C, enzyme (176 mg), and Celite (170 mg) in 1 : 1 mixture of chloroform and n-hexane as a solvent in the presence of K 2 CO 3 (as an inorganic base).
Dubey's research group in 1997 converted PA (1) to its monoesters through the reaction with simple alcohols (294) under a variety of conditions (Scheme 113). 266 The monoesters (295) could be prepared via two procedures: (A) reaction of PA and alcohols in a 1 : 2.2 molar ratio, in reuxing benzene, (B) reaction of PA with alkyl alcohols in 1 : 3.8 molar ratio in the presence of sodium alkoxide (0.02 g) at room temperature with 5 min. The diesters (296) were also obtained via various procedures: (I) reaction of PA and alcohols in 1 : 3.2 molar ratio in benzene solvent in the presence of p-TSA (5 mg) under reux conditions in a dean-stark apparatus within 6 h; (II) the reaction of PA with thionyl chloride (297) for 1 h under reux conditions, which was followed by separating thionyl chloride, and consequent addition of pyridine and an appropriate alcohol and reuxing for 3 h.
Fareghi-Alamdari's group also introduced two highly acidic, imidazolium-based, functionalized dicationic ionic liquids (FDCILs), which used (in 0.2 eq.) as efficient and green catalysts in the synthesis of phthalate plasticizers through the esterication of PA with alcohols (such as ethanol, n-propanol and n-butanol) at 110°C. Among these two FDCILs, (FDCIL 1: [(dimethyl-4-sulfobutyl-ammonium)-1,2-ethane-1H-imidazolium sulfonic acid]hydrogen sulfate and FDCIL 2: 3,3 ′ -(1,2ethanediyl)bis[1-(4-sulfobutyl)-1H-imidazolium sulfonic acid] hydrogen sulfate), the rst one performed better. The catalytic activity of FDCIL is related to the density of acidic groups on it (higher acidity) and the length of the carbon chain (low lipophilic character) in the cationic part. The inuences of the reaction temperature, catalyst dosage, and molar ratio of PA to alcohol on the esterication reaction were investigated. The reusability of the catalyst in these reactions was also studied. The yields were estimated by GC analysis. 268 Phthalate plasticizers are the main plasticizers used as soening agents in various industrial applications. These compounds are mainly used as plasticizers for cellulosic resins and some vinyl ester resins, PVC, and nitrocellulose lacquers. 269 Fareghi-Alamdari in 2018 also prepared supported diacidic ionic liquid on magnetic silica nanoparticles (SDAIL@magnetic nano SiO 2 ) and investigated its catalytic activity (10 mol%) for the selective diesterication of alcohols (2-methoxy ethanol, allyl alcohol, 2-ethoxyhexanol, butanol, propanol, ethanol, and methanol) with PA in a 5 : 1 molar ratio to afford the corresponding dialkyl plasticizers (296) under solvent-free conditions (65-180°C) within 1-10 h. Under the optimized conditions, the conversion of PA was 100%, and the diester plasticizers were obtained with excellent yields (80-100%). The SDAIL@magnetic nano-SiO 2 catalyst showed good reusability and could be easily separated from the reaction mixture using an external magnet, washed with dichloromethane, and reused for the next runs for up to 8 runs without signicant activity loss. 270 Shahedi and Mansoori in 2018 studied the esterication reaction of PA (1) with various aliphatic and cycloaliphatic alcohols (such as propanol and butanol) in the presence of a Fe 3 O 4 @SiO 2 -SO 3 H (5 mol%) nanocatalyst. The two mentioned alcohols gave the corresponding diesters (296) in duration of 8-12 h with a yield of 71-97%. 271 Kulawska's group in 2011 considered the kinetics of the syntheses of higher aliphatic alcohols (C7, C9, C11) phthalates in an isothermal, semi-batch reactor. In the rst stage of the process, the formation of monoester (295) was very fast and irreversible. In the second stage, the esterication of monoester toward diester (296) in the presence sulfuric acid catalyst progressed slowly. These reactions appeared to be rst order with respect to the monoester and did not depend on the concentration of the alcohol. 272 Mohammadpour  273 The kinetics of esterication of PA with 2-ethylhexanol was studied by Bhutada and Pangarkar in 1986 using three kinds of catalysts such as tetrabutyl titanate (TBT), tetrabutyl zirconate (TBZ), and p-TSA. In each case, the kinetic parameters such as rate constant (order with respect to various reactants and catalyst), activation energy, and collision frequency were determined. The titanates and zirconates were found to be better than p-TSA in rate and rate/product quality, respectively. The reaction shows general rst order in the monoester and alcohol. Bimolecular acyl oxygen ssion satisfactorily explains the kinetics. 274 Gharibe in 2020 utilized the novel ZnAl 2 O 4 /SiO 2 (5 mol%) for the esterication of PA with 2-ethylhexanol to obtain dioctyl phthalate (DOP) in 99.2% yield in 45 min. 275 Brennecke's group in 1994 surveyed the pressure effect on the bimolecular rate constants for the esterication of PA with methanol in supercritical carbon dioxide (SC CO 2 ) at 40°C and 50°C. They observed a 25-fold decrease in the bimolecular rate constant based on bulk concentrations when increasing the pressure from 97.5 to 166.5 bar. 276 Khodadadi Moghaddam and Gholami in 2006 inspected the esterication of PA with 2-octanol in the presence of sulfated titania (SO 4 2− /TiO 2 prepared by immersing titania powder in 1 N solution of sulfuric acid). The conversion reached an equilibrium composition in 20 min for dioctyl phthalate without water removal from the reactor. The linear dependence of conversion to the catalyst amount exhibited that there are no mass transfer limitations in the reaction conditions. 277 Yadav's group in 1992 represented the efficacy of several solid superacidic catalysts [such as phosphate, borated, and sulfated zirconia, sulphated iron oxide, phosphotungstic acid (P 2 O 5 $24WO 3 $nH 2 O), and dodecatungstophosphoric acid (H 3 -PO 4 $12WO 3 $nH 2 O)] in the preparation of the industrially important plasticizer dioctyl phthalate (DOP) from 2-ethylhexanol and PA. 278 Bajracharya et al. in 2021 prepared phthalate monoesters (295) and diesters (296) via the reaction of PA (1) and alcohols (allyl, isoamyl, n-butyl, and benzyl alcohols) (294) through a one-pot two-step procedure in the presence of FeCl 3 as Scheme 116 Phosphonodipeptides and homolog preparation procedure. a catalyst. Utilizing the reactants in a 1 : 2 molar ratio at 50°C achieved both the phthalate esters (295, 296). Addition of excess amounts of alcohol at 50°C or 100°C yielded the selective preparation of diesters (296). The authors claimed that the synthesis of the adducts (295) was performed through a facile addition displacement pathway, which was continued by Lewis acid catalysis providing phthalate diesters (296). The ring-closing metathesis of diallyl phthalate using the Grubb's 2nd generation catalyst led to macrolide (298) (Scheme 114). 279 Scheme 117 Novel phosphonodipeptide conjugates of ursolic acid and their homologs. Polyiuoroalkyl mono-and diesters of PA were obtained by Rakhimova and Kudashev in 2011 through the reaction of PA (1) with polyuorinated alcohols (299). The monesters (300) were achieved via the ultrasonic-assisted (40 kHz) reaction of equimolar amounts of PA and polyuorinated alcohol in cyclohexanone for 2 h at 70°C, which was followed by heating at 130°C for 2 h to complete the transition of phthalic anhydride. The diesters (301) were also prepared as the same procedure in the presence of PA : alcohols in a 1 : 2 molar ratio (Scheme 115). 280 Karimi Alavijeh and Amini in 2019 demonstrated that mesoporous MIL-101(Cr)-SO 3 H and [Cr 3 O(BDC-SO 3 H) 2.4 (BDC-SO 3 -NH 3 Bu) 0.6 ] n (20% BuNH 2 ) acted as potent and robust catalysts in the esterication of PA (1) with various alcohols in a 1 : 5 molar ratio under solvent-free conditions. 281 Aer the completion of the reaction, the catalyst was separated by centrifugation, washing with dichloromethane, drying at 50°C, and reusing in the next reaction for 6 runs without activity loss.

Conclusion
In this literature survey, the authors focused on applications of phthalic anhydride (PA), a cyclic fused heterocyclic anhydride, as a versatile substrate in organic reactions. Actually, PA is an efficient substrate and/or intermediate in several organic transformations due to its bifunctional cyclic anhydride moiety, which could be opened via the attack of various nucleophilic groups. In addition to the introduction part, which identied the compound and its overall utilities in various respects, the review has been subdivided into some parts, centralizing on the organic two-and multicomponent reactions containing PA as the substrate. The importance and applicability of PA in ester-ication are also discussed with examples. There is also a nal part that discusses the preparation of heterocycles starting from PA via multistep protocols, which possess various applications in pharmacology, treatment, natural products, industry, and some other elds of operative aspects of science and technology. In all the abovementioned parts, PA plays a crucial role as a substrate that cannot be changed with other heterocycles, which could be due to the intrinsic activity of the anhydride functional group. The authors hope that this review would be helpful and effectual for future research by chemists on PA and its analogs.

Conflicts of interest
There are no conicts to declare.